DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims included in prosecution are claims 1-2, 4-28, and 31.
Previous Rejections
Applicants' arguments in the Request for Continued Examination, filed February 24, 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
1. Claims 1-2, 5, 26-28, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2009/0169607, Jul. 2, 2009) (hereinafter Keller) in view of Hassan et al. (US 8,609,115, Dec. 17, 2013) (hereinafter Hassan) as evidenced by Yamaguchi et al. (US 2008/0213383, Sep. 4, 2008) (hereinafter Yamaguchi).
Keller teaches a liquid pharmaceutical composition containing: a) a therapeutically effective dose of a cyclosporin; b) an aqueous carrier liquid; c) a first solubilizing substance selected among the group of phospholipids; and d) a second solubilizing substance selected among the group of non-ionic surfactants (satisfies mixture of claim 1). Preferably, the cyclosporin is liposome solubilized (satisfies form of claim 1) (Abstract). The preferred cyclosporin is cyclosporin A (satisfies claim 28 & 31) (¶ [0025]). The liposomal preparation can be prepared by high-pressure homogenization. For example, the water-soluble components can be provided in the form of an aqueous solution into which the ciclosporin is dispersed and liposomes are subsequently formed by a high pressure homogenization process, wherein the size and the polydispersity index of the liposomes can be adjusted by varying the pressure and the number of cycles (satisfies dispersing & homogenizing of claim 1) (¶ [0051]). Preferably, the composition is sterile, especially when it is intended to be used for pulmonary application (¶ [0068]). Sterilization is carried out by sterile filtration subsequent to the homogenization (satisfies claim 26-27) (¶ [0071]). The compositions may be made by using the water-soluble adjuvants (sodium chloride, sodium citrate, citric acid and Tween 80). They are weighed into a 1 litre Erlenmeyer flask and are dissolved in water with stirring. Thereafter, the lecithin (Phospholipon G90), dexpanthenol, tocopherol acetate and the active agent (ciclosporin A) are added and dispersed with stirring. Thereafter, the mixture is homogenized for about 10 minutes in an UltraTurrax and transferred to a high pressure homogenizer. At about 1500 bar, the mixture is homogenized until a colloidal preparation is obtained. The colloidal preparation is subsequently sterile filtered under a dean bench and 20 ml thereof are filled into previously sterilized brown glass bottles which are closed with a pumping spray cap which allows multiple sterile withdrawal of the composition (satisfies limitations a) to c) of claim 1) (¶ [0079]).
Keller differs from the instant claims insofar as not reciting wherein the disperser used is a rotor-stator device and not disclosing the specific shear rate of the dispersing step.
However, Hassan discloses methods and systems for drug delivery utilizing high shear which comprise subjecting a therapeutic fluid containing a drug to high shear (Abstract). As used, the term "therapeutic fluids" refers to dispersions that contain at least one substance that has therapeutic effects (i.e., drug) (col 3, line 15-17). The devices used are rotor-stator type shear devices (col 3, line 60-65). Suitable actives for use include antibiotics (col 3, line 20). The desired shear rate may be in the greater than 20,000 s-1, or in some embodiments at least 40,000 s-1, or in some embodiments at least 100,000 s-1. In embodiments, the shear rate generated by a shear device is in the range of from 20,000 s-1 to 100,000 s-1 (col 5, line 46-55). In certain instances, shear device comprises an ULTRA-TURRAX® of IKA® Works, Inc (col 7, line 29-30). Selection of the shear device, shear rate, shear stress, and residence time applied in shear device depends on the amount of therapeutic fluid/dispersion administered and the nature of the components of the therapeutic fluids utilized. The operational parameters are further adjusted according to the objectives of tasks at hand, which dictate the specific requirements for the therapeutic fluids (col 9, line 62-67). The application of shear is especially useful in creating therapeutic dispersions/fluids wherein the therapeutic agents (drugs) are not miscible or soluble in the continuous phase (col 10, line 45-48). The fine dispersion of the drug combined with passage through the shear device allows for better absorption of drugs into the cells and tissues, thus making the drugs more effective and reducing adverse effects the drugs have on the liver. This also reduces the amount of drugs required because the liver is not filtering out the drugs (col 11, line 4-9).
As evidenced by Yamaguchi, cyclosporine A is a poorly water-soluble drug (¶ [0032]).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified the process/composition of Keller to utilize a rotor-stator shear device and a shear rate of greater than 20,000 s-1, or at least 40,000 s-1, or at least 100,000 s-1, or in the range of from 20,000 s-1 to 100,000 s-1, motivated by the desire to achieve a dispersion of the active in the continuous phase and achieve the finer dispersion of the active which results in better absorption of the drug and making the drug more effective and reduces its adverse effects and required amounts as taught by Hassan. One of ordinary skill in the art would have had a reasonable expectation of success since Hassan discloses that this high shear rate is generated from a high shear rate device such as an ULTRA-TURRAX (i.e., the same machine utilized by Keller) and discloses wherein the dispersion used is an aqueous one which comprises therapeutic agents.
Regarding the shear rate recited in claim 5, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As discussed above, Keller in view of Hassan disclose wherein the desired shear rate may be in the greater than 20,000 s-1, or in some embodiments at least 40,000 s-1. In embodiments, the shear rate generated by a shear device is in the range of from 20,000 s-1 to 100,000 s-1. Accordingly, because the ranges recited in the instant claims overlap with and/or lie inside the ranges disclosed by Keller in view of Hassan, the ranges disclosed by Keller in view of Hassan meet the instantly recited limitations.
Regarding the dispersion times recited in instant claims 21-22, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). As discussed above, Keller in view of Hassan disclose that selection of the residence time applied in shear device depends on the amount of therapeutic fluid/dispersion administered and the nature of the components of the therapeutic fluids utilized. The operational parameters are further adjusted according to the objectives of tasks at hand, which dictate the specific requirements for the therapeutic fluids. This renders it a result effective variable. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed dispersion times to yield the specifically desired dispersion depending on the amount/type of active used, the aqueous carrier used, and nature of the additives/excipients used in the mixture as well.
Therefore, the combined teachings of Keller and Hassan render obvious claims 1-2, 5, 26-28, and 31.
2. Claims 4, 8-9, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2009/0169607, Jul. 2, 2009) (hereinafter Keller) in view of Hassan et al. (US 8,609,115, Dec. 17, 2013) (hereinafter Hassan) and further in view of IKA (Data Sheet UTE 115, 2014) (hereinafter IKA-115).
The teachings of Keller and Hassan are discussed above.
The combined teachings of Keller and Hassan differ from the instant claims insofar not explicitly disclosing the specific UltraTurrax disperser used.
However, IKA-115 discloses that the ULTRA-TURRAX® UTE 115 is a is a high-performance dispersing machine which mixes, emulsifies, and disperses free-flowing or liquid media with a viscosity of up to 5.000 mPas in batch operation. Using the rotor-stator principle, the UTE is best suited for applications that cannot be accomplished using conventional stirring methods. The "P" version is equipped with a double-acting mechanical seal offering a reliable dry run safety (satisfies claim 2 & 4) (Page 1). The outer diameter of the dispersing tool for the UTE 115 – P is 115 mm (satisfies claim 8) (Page 2). The UTE has a rotational speed of 3,000 RPM (satisfies claim 9) (Technical Data). The UTE 115-P disperser has a tip speed of 15 m/s (satisfies claim 20) (Technical Data).
As noted by Page 55, Lines 4-5, of the instant specification, the ULTRA-TURRAX® UTE 115-P is an immersion disperser.
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified the method of Keller to include the use of an ULTRA-TURRAX® UTE 115-P motivated by the desire to utilize a disperser which is suited for applications that cannot be accomplished using conventional stirring methods and offers reliable dry run safety as taught by IKA-115.
Alternatively, generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Keller discloses wherein an ULTRA-TURRAX disperser was used to prepare their mixture. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to have modified the method of Keller to include the use of an ULTRA-TURRAX® UTE 115-P, since it is a known ULTRA-TURRAX disperser for use in mixing/dispersing free-flowing or liquid media as taught by IKA-115.
Therefore, the combined teachings of Keller, Hassan, and IKA-115 render obvious claims 4 and 8-9.
3. Claims 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2009/0169607, Jul. 2, 2009) (hereinafter Keller) in view of Hassan et al. (US 8,609,115, Dec. 17, 2013) (hereinafter Hassan) and further in view of Luciani (Org. Process Res. Dev. 2018, 22, 1328−1333) (hereinafter Luciani).
The teachings of Keller and Hassan are discussed above.
The combined teachings of Keller and Hassan differ from the instant claims insofar as not disclosing the specific shear frequencies used.
However, Luciani discloses that in the pharmaceutical industry, the design and optimization of high-shear rotor−stator wet milling (HSWM) operations are still highly empirical. Parameters such as the rotor tip speed, average shear rate, shear frequency, and shear number are used to scale the mill rotation rate up or down (Introduction).
Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). As discussed above, Luciani that parameters such as shear frequency are used to scale the high-shear rotor−stator mill rotation rate up or down, which makes amounts thereof a result effective variable, since shear frequency directly impacts the mill rotation rate. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed shear frequencies of about 50,000 1/s to about 80,000 1/s to yield the desired mill rotation rate.
Regarding the shear rate recited in claim 7, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As discussed above, Keller in view of Hassan disclose wherein the desired shear rate may be in the greater than 20,000 s-1, or in some embodiments at least 40,000 s-1. In embodiments, the shear rate generated by a shear device is in the range of from 20,000 s-1 to 100,000 s-1. Accordingly, because the ranges recited in the instant claim overlap with and/or lie inside the ranges disclosed by Keller in view of Hassan, the ranges disclosed by Keller in view of Hassan meet the instantly recited limitations.
Therefore, the combined teachings of Keller, Hassan, and Luciani render obvious claims 6-7.
4. Claims 10-11 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2009/0169607, Jul. 2, 2009) (hereinafter Keller) in view of Hassan et al. (US 8,609,115, Dec. 17, 2013) (hereinafter Hassan) and further in view of IKA (Data Sheet UTL 1000/10, 2011) (hereinafter IKA-1000)
The teachings of Keller and Hassan are discussed above.
The combined teachings of Keller and Hassan differ from the instant claims insofar as not explicitly disclosing the specific UltraTurrax disperser used.
However, IKA-1000 discloses that the ULTRA-TURRAX® UTL 1000/10 is lower-priced, particularly multifunctional and used for mixing, dispersing, emulsifying/suspending, and homogenizing of solid and liquid substances up to viscosities of several thousand mPa·s (Page 1). The UTL 1000/10 has a rotational speed of 3600 RPM (satisfies claim 16) (Technical Data).
As noted by Page 56, Lines 6-7, of the instant specification, the ULTRA-TURRAX® UTL 1000/10 is an inline disperser that has a diameter of 119.4 mm.
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified the method of Keller to include the use of an ULTRA-TURRAX® UTL 1000/10 motivated by the desire to utilize a lower priced and particularly multifunctional machine which is suited for mixing, dispersing, emulsifying/suspending, and homogenizing of solid and liquid substances up to viscosities of several thousand mPa·s as taught by IKA-1000.
Alternatively, generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Keller discloses wherein an ULTRA-TURRAX disperser was used to prepare their mixture. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to have modified the method of Keller to include the use of an ULTRA-TURRAX® UTL 1000/10, since it is a known ULTRA-TURRAX disperser for use in mixing/dispersing solid and liquid substances as taught by IKA-1000.
Regarding the shear rate recited in instant claims 11, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As discussed above, Keller in view of Hassan disclose wherein the desired shear rate may be in the greater than 20,000 s-1, or in some embodiments at least 40,000 s-1. In embodiments, the shear rate generated by a shear device is in the range of from 20,000 s-1 to 100,000 s-1. Accordingly, because the ranges recited in the instant claim overlap with and/or lie inside the ranges disclosed by Keller in view of Hassan, the ranges disclosed by Keller in view of Hassan meet the instantly recited limitations.
Therefore, the combined teachings of Keller, Hassan, and IKA-1000 render obvious claims 10-11 and 15-16.
5. Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2009/0169607, Jul. 2, 2009) (hereinafter Keller) in view of Hassan et al. (US 8,609,115, Dec. 17, 2013) (hereinafter Hassan) and IKA (Data Sheet UTL 1000/10, 2011) (hereinafter IKA-1000) and further in view of Luciani (Org. Process Res. Dev. 2018, 22, 1328−1333) (hereinafter Luciani).
The teachings of Keller, Hassan, and IKA are discussed above.
The combined teachings of Keller, Hassan, and IKA-1000 differ from the instant claims insofar as not explicitly disclosing the shear frequencies of the dispersing step.
However, Luciani discloses that in the pharmaceutical industry, the design and optimization of high-shear rotor−stator wet milling (HSWM) operations are still highly empirical. Parameters such as the rotor tip speed, average shear rate, shear frequency, and shear number are used to scale the mill rotation rate up or down (Introduction).
Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). As discussed above, Luciani that parameters such as shear frequency are used to scale the high-shear rotor−stator mill rotation rate up or down, which makes amounts thereof a result effective variable, since shear frequency directly impacts the mill rotation rate. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed shear frequencies to yield the desired mill rotation rate.
Regarding the shear rate recited in claim 14, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As discussed above, Keller in view of Hassan disclose wherein the desired shear rate may be in the greater than 20,000 s-1, or in some embodiments at least 40,000 s-1. In embodiments, the shear rate generated by a shear device is in the range of from 20,000 s-1 to 100,000 s-1. Accordingly, because the ranges recited in the instant claim overlap with and/or lie inside the ranges disclosed by Keller in view of Hassan, the ranges disclosed by Keller in view of Hassan meet the instantly recited limitations.
Therefore, the combined teachings of Keller, Hassan, IKA-1000, and Luciani render obvious claims 12-14.
6. Claims 17-19 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2009/0169607, Jul. 2, 2009) (hereinafter Keller) in view of Hassan et al. (US 8,609,115, Dec. 17, 2013) (hereinafter Hassan) and IKA (Data Sheet UTE 115, 2014) (hereinafter IKA-115) and further in view of IKA (Data Sheet UTL 1000/10, 2011) (hereinafter IKA-1000).
The teachings of Keller, Hassan, and IKA-115 are discussed above and differ from the instantly recited claims insofar as not explicitly disclosing wherein an immersion and inline disperser are both used.
However, as discussed above, the UTE 115-P is an immersion disperser and the UTL 1000/10 disperser is an inline disperser.
Generally, it is prima facie obvious to combine two compositions, each of which is taught by the prior art to be useful for same purpose, in order to form a third composition to be used for the very same purpose. The idea for combining them flows logically from their having been individually taught in the prior art. See MPEP 2144.06. Therefore, it would have been obvious for one of ordinary skill in the art to use two different ULTRA-TURRAX dispersers (i.e., ULTRA-TURRAX® UTE 115-P (immersion) and UTL 1000/10 (inline)) when used for the same purpose since Keller suggests using two homogenizers/dispersers and one of ordinary skill in the art would reasonably conclude that utilizing both dispersers consecutively would result in an improved dispersion.
Regarding the dispersion times recited in instant claim 23, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. See MPEP 2144.05(II)(A). As discussed above, Keller in view of Hassan disclose that selection of the residence time applied in shear device depends on the amount of therapeutic fluid/dispersion administered and the nature of the components of the therapeutic fluids utilized. The operational parameters are further adjusted according to the objectives of tasks at hand, which dictate the specific requirements for the therapeutic fluids. This renders it a result effective variable. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed dispersion times to yield the specifically desired dispersion depending on the amount/type of active used, the aqueous carrier used, and nature of the additives/excipients used in the mixture as well.
Therefore, the combined teachings of Keller, Hassan, IKA-115, and IKA-1000 render obvious claims 17-19 and 23.
7. Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (US 2009/0169607, Jul. 2, 2009) (hereinafter Keller) in view of Hassan et al. (US 8,609,115, Dec. 17, 2013) (hereinafter Hassan) and further in view of Miller et al. (US 5,246,624, Sep. 21, 1993) (hereinafter Miller).
The teachings of Keller and Hassan are discussed above.
The combined teachings of Keller and Hassan differ from the instant claims insofar as not explicitly disclosing wherein a filtration step is used prior to sterile filtration.
However, Miller discloses that the ability of a dispersion to pass through a filter is also related to the viscosity of a dispersion. The finer the filter, i.e. the smaller the size of
the pores of the filter, the lower the viscosity of the aqueous colloidal dispersion must be to pass through the filter (col 1, line 65-68). Further, to increase purity, the colloidal dispersion should be passed through as fine a filter as possible (col 2, line 2-4). The colloidal dispersion will typically go through a 250 micron or smaller pore size filter (col 3, line 10-13).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified the method of Keller to include a filtration step using a filter with a pore size of 250 microns or less motivated by the desire to achieve a composition with lower viscosity and higher purity as taught by Miller.
Therefore, the combined teachings of Keller, Hassan, and Miller render obvious claims 24-25.
Response to Arguments
Regarding Applicant’s arguments with respect to the previous rejections in view Keller and the homogenization pressure being a result effective variable, upon further search, the Examiner found Hassan teaches shear rates for aqueous dispersions of therapeutic compositions which overlap with those instantly claimed and provides motivation for utilizing/adjusting said shear rates. Furthermore, the Examiner found Luciani provides strong motivation to adjust/optimize shear frequencies in therapeutic compositions which utilize shear rotor-stator devices. Accordingly, and while not agreeing, Applicant’s arguments with respect to the previous routine optimization argument are moot at this time.
Regarding Applicant’s arguments which refer/pertain to the Declaration submitted Feb. 24, 2026 and the allegations of unexpected results recited therein, please refer to the Response to Declaration below.
Regarding Applicant’s arguments that IKA-115 fails to cure the alleged deficiencies of Keller, the Examiner submits that IKA-115 cures any alleged deficiencies of Keller where IKA-115 discloses that the ULTRA-TURRAX® UTE 115 is a rotor-stator disperser and discloses its diameter, rotational speed, and tip speed and provides strong motivation for its use where they disclose that the ULTRA-TURRAX® UTE 115 is a disperser which is suited for applications that cannot be accomplished using conventional stirring methods and offers reliable dry run safety.
Regarding Applicant’s arguments that IKA-1000 fails to cure the alleged deficiencies of Keller, the Examiner submits that IKA-1000 cures any alleged deficiencies of Keller where IKA-1000 discloses the rotational speed and tip speed of the ULTRA-TURRAX® UTL 1000/10 and provides strong motivation for its use where they discloses that it is a lower priced and particularly multifunctional machine which is suited for mixing, dispersing, emulsifying/suspending, and homogenizing of solid and liquid substances up to viscosities of several thousand mPa·s.
Regarding Applicant’s arguments that Miller fails to cure the alleged deficiencies of Keller, the Examiner submits that Miller cures any alleged deficiencies of Keller where Miller provides strong motivation for including a filtration step using a filter with a pore size of 250 microns or less where they disclose that using a filter with a pore size of 250 microns or less results in a composition with lower viscosity and higher purity.
In light of the foregoing, the Examiner does not find Applicant’s arguments to be persuasive and the rejection is maintained.
Response to Declaration by Oliver Denk Submitted Feb. 24, 2026
Regarding Applicant’s arguments with respect to the previous rejections in view Keller and the homogenization pressure being a result effective variable, upon further search, the Examiner found Hassan which teaches shear rates for aqueous dispersions of therapeutic compositions which overlap with those instantly claimed and provides motivation for utilizing/adjusting said shear rates. Furthermore, the Examiner found Luciani which provides strong motivation to adjust/optimize shear frequencies in therapeutic compositions which utilize shear rotor-stator devices. Accordingly, and while not agreeing, Applicant’s arguments with respect to the previous routine optimization argument are moot at this time.
Regarding Applicant’s argument with respect to the relationship between high shear rates and foaming, as a threshold matter, the Examiner submits that while higher shear rates/mixing speeds are related to foam formation in some cases, one of ordinary skill in the art would recognize that this is not a linear relationship. Foam formation is a complex process that depends on multiple parameters and variables. Shear rate/velocity is a readily adjustable variable known to materially affect dispersions in different ways, as discussed in the rejection above. One of ordinary skill in the art would have been motivated to adjust shear rate/velocity in both directions (higher and lower), as part of routine optimization since selection of the shear rate applied in shear device depends on the amount of therapeutic fluid/dispersion administered and the nature of the components of the therapeutic fluids utilized. The operational parameters are further adjusted according to the objectives of tasks at hand, which dictate the specific requirements for the therapeutic fluids as taught by Hassan. As such, using a higher shear rate/velocity such as the one claimed would have been obvious for one of ordinary skill in the art to try, with a reasonable expectation of success in improving the overall outcome of the mixture. Second, Applicant’s assertion that “a skilled scientist would not be motivated to explore high dispersion shear rates/velocities because a sparingly soluble active pharmaceutical active ingredient such as cyclosporine A introduced into a foam-generating carrier liquid or solution may be incorporated into the foam”, is directly contradicted by disclosures of the art such as Hassan which discloses shear rates that overlap with those claimed and those that are even higher for actives that are not soluble in the continues phase. Specifically, Hassan attributes the improvement in their solubility to the higher shear rate. As such, in view of the art, one of ordinary skill in the art would indeed have been motivated to explore high dispersion shear rates.
Regarding allegations of unexpected results, Applicant has the burden of explaining the data in any declaration they proffer as evidence of non-obviousness. MPEP § 716.02(b)(II).
Applicant has not adequately explained the results. For instance, it is entirely unclear
how the total amount of cyclosporine A was measured.
Moreover, any differences between the claimed invention and the prior art may be expected to result in some difference in properties. The issue is whether the properties differ to
such an extent that the difference is really unexpected. The burden is on applicant to establish
that the results are in fact really unexpected and of statistical and practical significance. Ex
parte Gelles, 22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992). See also MPEP § 716.02.
Applicant does not appear to have discussed same with respect to objective data. Furthermore, Applicant’s data does not appear to be unexpected since the mixture from Ex. 2, which had a cyclosporine A content of 95.47%, was subjected to dispersion conditions that were significantly different than the dispersion from Ex. 1. For instance, the Ex. 2 mixture was dispersed for only 80 minutes, while the Ex. 1 mixture was dispersed for 8 hours (6x the dispersion time). In addition, the Ex. 2 mixture was subjected to a rotational speed of only 3,000 rpm, while the Ex. 1 mixture was subjected to 4,800 rpm (1.6x the rotational speed). Finally, the Ex. 2 mixture was subjected to a shear frequency of only 40,500 1/s, while the Ex. 1 mixture was subjected to 64,800 1/s (1.6x the shear frequency).
While Applicant alleges that the conditions of Ex. 1 would “potentially” have resulted in increased foam as compared to the conditions of Ex. 2, this does not negate the fact that it would be reasonable for one of ordinary skill in the art to conclude that dispersing the mixture for a much longer period of time and subjecting it to significantly higher rotational speeds and shear frequencies would materially affect the amount of active in the resulting dispersion. Furthermore, the alleged potential increase in foam formation does negate the fact that it would be reasonable for one of ordinary skill in the art to conclude that an active that is allegedly so sensitive to shear rate would be at least equally sensitive to dispersion time, rotational speed, and shear frequency. As such, it is unclear if the results are indeed “unexpected”.
Regarding Applicant’s newly tested examples, Applicant’s data does not appear to be unexpected since critical information is not compared and Ex. 1B was subjected to dispersion conditions that were significantly different than the dispersion from Ex. 1. For instance, the shear frequencies of Ex. 1A and 1B were not compared and were not shown to be closer as alleged to those of Ex. 2. Furthermore, the Ex. 2 mixture was dispersed for only 80 minutes, while the Ex. 1B mixture was dispersed for 4 hours (3x the dispersion time). In addition, the Ex. 2 mixture was subjected to a rotational speed of only 3,000 rpm, while the Ex. 1B mixture was subjected to 4,600 rpm (1.5x the rotational speed). As such, it is unclear if the results are indeed “unexpected”.
As a threshold matter, the Examiner thanks Applicant for pointing out the inadvertent mistake made in the previously mailed action with respect to the cited shear rate as it relates to being commensurate in scope.
Finally, assuming purely arguendo that unexpected results have been established, the Applicant must explain the “manner in which the specific compositions illustrated are considered to be commensurate in scope with the claimed invention”; see Ex parte Gelles, 22 USPQ2d 1318 (Bd. Pat. App. & Inter. 1992); see also MPEP 716.02, citing same.
For instance, Applicant’s claim 1 merely requires the presence of an inhalable immunosuppressive macrocyclic active ingredient generically. However, the examples tested contain only cyclosporine A. As such, it is unclear if only cyclosporine A responds in this manner to the claimed shear rate, or if all inhalable immunosuppressive macrocyclic active ingredients encompassed by the instant claims do. Further, it is not clear if the results would vary if other inhalable immunosuppressive macrocyclic active ingredients were used in place of cyclosporine A. In order for this to be established, cyclosporine A must be reasonably representative of inhalable immunosuppressive macrocyclic active ingredients in general. However, no evidence of this has been provided. As such, Applicant’s data is not commensurate in scope with the instant claims.
Furthermore, Applicant’s claim 1 merely requires the presence of a phospholipid and a non-ionic surfactant generically. However, the examples tested contain only soybean lecithin Lipoid S100 and polysorbate 80. As such, it is unclear if only soybean lecithin Lipoid S100 and polysorbate 80 responds in this manner with the claimed shear rate, or if all phospholipids and a non-ionic surfactants encompassed by the instant claims do. Further, it is not clear if the results would vary if other phospholipids and a non-ionic surfactants were used in place of soybean lecithin Lipoid S100 and polysorbate 80. In order for this to be established, soybean lecithin Lipoid S100 and polysorbate 80 must be reasonably representative of phospholipids and non-ionic surfactants in general. However, no evidence of this has been provided. As such, Applicant’s data is not commensurate in scope with the instant claims.
Regarding Applicant’s argument’s that they “believe” that it is “likely” that other inhalable immunosuppressive macrocyclic active ingredients would behave similarly to cyclosporine A, the Examiner submits that arguments presented by Applicant cannot take the place of evidence in the record. See also MPEP § 2145(I). Additionally, factually uncorroborated assertions (such as those referenced in the specification) cannot take the place of evidence in the record. See MPEP § 716.01 (c)(II). While Applicant points to the fact that cyclosporine A, tacrolimus, sirolimus, and everolimus have similar molecular weights, solubility in organic solvents, and microgram solubility, the Examiner points to the fact that these four actives are not the only ones encompassed by the very broad recitation of inhalable immunosuppressive macrocyclic active ingredients recited by the instant claims. Furthermore, properties such as the aforementioned ones or such as polarity, lipophilicity, and hydrogen bonding are not the only factors at play when considering whether a compound is reasonably representative of a class of compounds. There are many other chemical properties of a compound not considered by Applicant, which one of ordinary skill in the art would not consider to be interchangeable, and any one of which may render said compound an outlier within its class.
Furthermore, Applicant’s claim 1 requires a shear rate with a very broad range of 25,000 1/s to 125,000 1/s. However, the shear rate used in most of the inventive examples (i.e., Ex. 1, Ex. 1A, & Ex. 1B) was around 32,000 1/s – 33,000 1/s, which is very specific. While Applicant points to Ex. 3 which had a shear rate of 71,413 1/s, this is again a very specific value that is very far from the higher end of the recited range and as such, a trend cannot be reasonably established. Therefore, the probative value of the data cannot be reasonably extended across the full breadth of the claimed range since a trend cannot be reasonably determined. As such, it is unclear if the noted improvement in drug loading is related to the shear rate used or if it is related to other dispersion conditions the mixture may have been subjected to. Therefore, Applicant’s data is not commensurate in scope with the instant claims.
As such, the Examiner finds that the Declaration is insufficient to overcome the rejection of record and the rejection is maintained.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
1. Claims 1-2, 4-28, and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 3-13, 15, and 30 of copending Application No. 18/317,940 in view of Knoch (WO 2016/146645, Sep. 22, 2016) (hereinafter Knoch)
The copending claims differ from the pending claims insofar as reciting wherein the composition is lyophilized and reciting specific phospholipids and nonionic surfactants.
However, Knoch discloses cyclosporine formulations for use in the prevention or treatment of pulmonary chronic graft rejection (Abstract). These formulations comprise a therapeutically effective dose of a cyclosporine, an aqueous carrier liquid, a first solubility enhancing substance selected from the group of phospholipids and a second solubility enhancing substance selected from the group of non-ionic surfactants” (p. 8, lines 23-26). Wherein the phospholipid is a mixture of natural phospholipids, such as lecithins (p. 9, line 1) and the non-ionic surfactant may be polysorbate 80 (p. 8, lines 3-4). Knoch also discloses the composition may be freeze-dried (i.e., lyophilized) (p. 9, line 17).
Accordingly, it would have been obvious for one of ordinary skill in the art to have formulated the method/composition of the pending claims to comprise the specific phospholipids and nonionic surfactants of the copending claims since these are known solubility enhancing substances for use in compositions comprising cyclosporine as taught by Knoch. Further, it would have been obvious for one of ordinary skill in the art to have formulated the resulting composition of the pending claims to be lyophilized since this is a known use of such compositions as taught by Knoch.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-2, 4-28, and 31 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Abdulrahman Abbas whose telephone number is (571)270-0878. The examiner can normally be reached M-F: 8:30 - 5:30.
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/A.A./Examiner, Art Unit 1612
/LEZAH ROBERTS/Primary Examiner, Art Unit 1612
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